tbuckley/cabot-search huggingface dataset:
OUTC-10. SELF-REPORTED RACE AND ETHNICITY AND GENETIC ANCESTRY GROUPS SHOW DISTINCT PREVALENCE AND OUTCOMES ACROSS PEDIATRIC CENTRAL NERVOUS SYSTEM TUMORS
Authors: Ryan Corbett, Alexa Plisiewicz, Sean McHugh, Emmett Drake, Miguel A Brown, Bo Zhang, Chuwei Zhong, Charnpreet Kaur, Philip B Storm, Adam Resnick, Sebastian Waszak, Sabine Mueller, Jo Lynne Rokita, Cassie Kline
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND Race and ethnicity disparities have been identified in survival of pediatric central nervous system (CNS) tumors. No prior studies have investigated the comparative effects of self-identified race and ethnicity versus genetic ancestry on tumor prevalence and outcome. We examine these contributions in a retrospective analysis of pediatric patients with CNS tumors. METHODS Patients from Children’s Brain Tumor Network (CBTN; n=646) and Pacific Pediatric Neuro-Oncology Consortium (PNOC; n=35) with available clinical data and whole genome sequencing were included. Ancestry groups were predicted with somalier and genetic markers from reference individuals of known ancestry that participated in the 1000 Genomes Project: sub-Saharan African (AFR), admixed American (AMR), East Asian (EAS), European (EUR), and South Asian (SAS). Independence of predicted ancestry and self-reported race and ethnicity was assessed with chi-squared tests. Effects of predicted ancestry on survival were estimated using multivariate Cox models with molecular subtype and extent of tumor resection as covariates. RESULTS Predicted ancestry groups were highly concordant with self-reported race (χ2=897, p&amp;lt;0.001) and ethnicity (χ2=340, p&amp;lt;0.001). Patients from AFR ancestry were significantly enriched within ATRT (n=26; p=0.001) and neurofibroma plexiform (n=11; p=0.005) and patients with AMR ancestry were enriched within DMG (n=53; p&amp;lt;0.001). Patients diagnosed with H3 wildtype high-grade glioma (n=39) with non-EUR ancestry trended towards worse overall survival (OS; HR=2.0, p=0.07). Patients with ATRT (n=19) with AMR ancestry trended towards worse OS compared to AFRs (HR=4.1, p=0.09) and AFR patients with MB (n=78) trended toward worse OS compared to EUR patients (HR=3.7, p=0.07), including Group 4 MBs (n=39; HR=3.9, p=0.08). Patients with LGG (n=182) with non-EUR ancestry were more likely to have less than gross total/near total resection compared to patients with EUR ancestry (p=0.02). CONCLUSIONS Differences in ancestry are seen across pediatric CNS tumor entities and outcomes. Analyses are underway in an additional ~800 patients.
XRT-04. THE ROLE OF STEREOTACTIC RADIOSURGERY FOR MENINGIOMAS IN PEDIATRIC PATIENTS
Authors: Regan Shanahan, Zhishuo Wei, Tracy Miller, Hansen Deng, Ajay Niranjan, L Dade Lunsford
Journal: Neuro-Oncology (2023)

Abstract Despite the generally benign and slow-growing nature, meningiomas in pediatric populations often exhibit more aggressive behavior. Stereotactic radiosurgery (SRS) is a non-invasive modality that is widely used as an upfront or adjuvant treatment for patients with meningiomas. Due to the rarity of meningiomas in pediatric patients, the outcomes of SRS for childhood meningiomas have never been described. From 1987 to 2022, a total of 2,030 patients with meningiomas underwent SRS at the University of Pittsburgh Medical Center. Nine patients (2 female; incidence rate = 0.44%) with a median age of 14.5 years (range, 9—17 years) at SRS were identified. Three patients (33.3%) had a history of total body irradiation. Seven patients (77.8%) were asymptomatic at the time of SRS presentation. Seven patients (77.8%) had a pre-SRS craniotomy; two patients (22.2%) had pre-SRS fractionated radiotherapy. The median cumulative tumor volume was 3.65 cc (range, 0.01—11.84 cc). The median margin dose prescribed was 14 Gy (range, 11—25 Gy). The median follow-up time was 107 months (range, 24—194 months). Five patients (55.6%) experienced tumor progression at a median of 25 months (range, 13—161 months). Local tumor control at 1-, 5-, and 10 years was 100%, 55.56%, and 55.56%, respectively. After local tumor progression, 2 patients received repeat SRS, 2 patients had surgical resection and 1 was placed on hydroxyurea for an unresectable tumor. At the date of the last clinical follow-up, 5 patients (55.6%) were still alive while 4 patients (44.4%) expired due to the progression of intracranial disease. 1-, 5-, and 10-year survival was 100%, 88.89%, and 64.81%, respectively. Childhood meningioma is a rare tumor that exhibits aggressive behaviors. SRS should be considered as an upfront or adjuvant treatment option in the multi-modal management of childhood meningiomas for optimal tumor control and maximal quality of life preservation.
ATRT-14. ASSESSMENT OF MITOCHONDRIAL BIOENERGETICS AND FISSION-FUSION DYNAMICS IN ETMR
Authors: Evangelos Liapis, Annapurna Pamreddy, Allison Maas, Derek Hanson, Claire Carter
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND Embryonal tumor with multilayered rosettes (ETMR) is a deadly pediatric brain tumor with limited available therapeutic options. Dysregulated mitochondrial bioenergetics and dynamics have been linked to the initiation and progression of diverse human cancers, however, their role in ETMR pathobiology remains unknown. We used the primary ETMR cell line, BT183, and an in-house developed human neural stem cell (NSC) line to evaluate mitochondrial morphology, bioenergetics and fission-fusion dynamics involved in ETMR growth and aggression. METHODS Mitochondrial morphology was determined by widefield immunofluorescence and dSTORM super-resolution microscopy in BT183 and NSC monolayers and by TEM in BT183 and NSCs grown as neurospheres. Relative expression of mitochondrial proteins were quantified in BT183 and NSC lysates by western blotting. RESULTS Widefield immunofluorescence and super-resolution imaging revealed profound differences in mitochondrial morphology in BT183 compared to NSCs. BT183 mitochondria appear as fragmented, rounded structures, with little interconnectivity, while NSC mitochondria present a typical elongated, filamentous morphology. These findings were corroborated by TEM image analysis of BT183 and NSC neurospheres, which revealed additional morphological alterations in BT183 mitochondria at the ultrastructural level, including aberrant cristae structure. Western blot analysis of BT183 and NSC lysates showed up to 5-fold differential expression of mitochondrial OXPHOS, glycolytic and fission-fusion proteins in the two cell types. Fission promoters phospho-Drp1 and MFF displayed significantly higher expression in BT183 relative to NSCs, whereas fusion-inducing proteins Opa1 and Miro2 showed significantly lower differential expression in BT183. CONCLUSIONS BT183 cells exhibited striking mitochondrial fragmentation and differential expression of proteins involved in fission-fusion, OXPHOS and glycolysis when compared to normal human NSCs. Ongoing studies include the analysis of mitochondrial structure and morphology in patient samples to validate our in-vitro findings, in addition to in-vitro metabolic flux analysis and targeted protein depletion studies to identify druggable pathways based on mitochondrial function and dynamics.
SURG-05. MRI-GUIDED FOCUSED ULTRASOUND BLOOD-BRAIN BARRIER DISRUPTION INCREASES DRUG DELIVERY AND EFFICACY IN AN ORTHOTOPIC DIPG MODEL
Authors: Payton Martinez, Genna Nault, Jenna Steiner, Michael Wempe, Angela Pierce, Breaunna Brunt, Mathew Slade, Andrew Mongin, Jane Song, Kang-Ho Song, Nicholas Ellens, Natalie Serkova, Adam Green, Mark Borden
Journal: Neuro-Oncology (2023)

Abstract Diffuse intrinsic pontine glioma is the most common and deadliest pediatric brainstem tumor and is difficult to treat with chemotherapy in part due to the blood-brain barrier (BBB). Focused ultrasound (FUS) and microbubbles (MBs) have been shown to cause BBB disruption (BBBD), allowing larger chemotherapeutics to enter the parenchyma. Panobinostat is an example of a promising in vitro agent in DIPG with poor BBB penetrance. In this study, we hypothesized that using FUS to disrupt the BBB allows higher concentrations of panobinostat to accumulate in the tumor, providing a therapeutic effect. Mice were orthotopically injected with a patient-biopsied DIPG cell line, BT-245. After two weeks of growth, MR images guided FUS targeting to the tumor location. Microbubbles (25µl/kg, IV) and FUS (Frequency: 1.515 MHz, PNP: 0.77MPa, PRF: 1Hz, PL: 10ms, treatment time: 3 minutes) were applied to half the mice. Passive cavitation data (PCD) was collected and analyzed. Panobinostat was given (10mg/kg IP) to all mice. After 1.5 hours, a subset of mice were sacrificed to determine the concentration of panobinostat in tumor and cortex areas. We showed a 3-fold drug concentration increase in the tumor region while only slightly increasing the concentration in the forebrain. The remaining mice received three weekly treatments. Half were treated with FUS/MB and panobinostat, while others received panobinostat only. MRI was taken weekly to evaluate BBBD extent and tumor growth. PCD during treatments showed ideal cavitation of microbubbles illustrating safety and consistency across all treatments. The combination of panobinostat and FUS exhibited a tumor size decrease of 71% on MRI compared to panobinostat alone. Furthermore, FUS/MB improved the mean survival from 21 to 31.5 days (p=0.0001). Our study demonstrates that FUS-mediated BBBD can increase the delivery of panobinostat to an orthotopic DMG tumor, providing a strong therapeutic effect and increased survival.
BIOL-06. UNDERSTANDING OLIGODENDROCYTE PROGENITOR CELL CONTRIBUTION TO GLIOMAGENESIS USING A NOVEL PHARMACOGENETIC ABLATION TOOL
Authors: Lulu Xing, Tobias Merson, Claudia Petritsch
Journal: Neuro-Oncology (2023)

Abstract In the central nervous system (CNS), gliomas represent almost 50% of all pediatric tumors and due to their complex histological and biological heterogeneity, aggressive standard treatment consisting of surgery and chemoradiotherapy remains ineffective. As a result, more biologically based therapies are urgently needed, and this requires a deeper knowledge of the etiology and biology of gliomas and the tumor microenvironment. Oligodendrocyte progenitor cells (OPCs) are a potential origin of human gliomas (as suggested by studies in genetically engineered mouse models) and human OPC-like tumor cells contribute to tumor heterogeneity and malignancy. Resident (non-neoplastic) OPCs have been found to intermix with glioma cells and proliferate within the tumor microenvironment. The significance of the interactions of resident OPCs and glioma cells remains unknown. We hypothesize that resident OPCs functionally integrate into the tumor cell network and affect tumor properties. We have generated a novel mouse model of conditional OPC ablation to overcome methodological challenges of most current approaches that often result in partial and transient OPC ablation, which limits our understanding of long-term function of OPCs. Here in our study, we have successfully developed a novel pharmacogenetic model of conditional OPC ablation, eliminating 98.6% of all OPCs throughout the mouse brain for up to 12 days post ablation. In the future, we plan to combine the mouse model of complete OPC ablation with orthotopic glioma models to reveal the longitudinal and spatial functional roles and the necessity for resident OPCs in the tumor context. Understanding the OPC-tumor cell crosstalk by using our state-of-the-art approach at both cellular and molecular levels will have significant clinical implications for improving treatment for patients with pediatric gliomas.
IMMU-09. DISSECTING THE INTERPLAY BETWEEN THE ENDOGENOUS IMMUNE RESPONSE AND ONCOLYTIC VIRUS THERAPY IN PEDIATRIC BRAIN TUMORS
Authors: Owen Hoare, Jangham Jung, Akihito Inagaki, Bohyeon Yu, Sara Collins, Polly Chuntova, Maria Barcova, Trishna Patel, Noriyuki Kasahara, Sabine Müller, Aaron Diaz
Journal: Neuro-Oncology (2023)

Abstract Oncolytic virus (OV) elicits an antitumor immune response in addition to tumor-cell killing. However, it is unknown if a pre-existing antitumor immune response aids or hinders OV therapy. To study the interplay between the endogenous immune response and OV we profiled tumors from immunocompetent intracranial models of medulloblastoma and glioblastoma treated with measles virus (MV) and retrovirus (Toca-511), using single-cell and bulk-RNA sequencing. For both models, we assayed specimens from two treatment groups, a mid-treatment group where mice were sacrificed upon observation of treatment response, and a post-treatment group where treatment-resistant mice were sacrificed when they had succumbed to their disease. As controls, we included a cohort treated with heat-inactivated virus and a cohort treated with PBS. Both MV and Toca-511 OV therapies significantly improve survival compared to controls. From each of the MV and Toca-511 treatment/control groups, 3 mice per group were profiled via RNA sequencing. Additionally, tumors from 5 mice treated with MV alone and 4 mice treated with MV and anti-PD1 immune-checkpoint blockade (ICB) were subjected to single-cell RNA sequencing (scRNA-seq). ScRNA-seq generated 38,491 cells after filtering for quality control and successfully captured both endogenous and viral RNAs. We found that in samples treated with both OV and ICB there were higher rates of virally infected cells, depletion of M2-polarized myeloid infiltrates, and depletion of endothelial cells, compared to controls. Comparing virally infected tumor cells to non-infected controls we observed a down-regulation of translation initiation-complex genes and an upregulation of markers of oxidative phosphorylation. Infected cells from treatment-resistant tumors upregulate antigen presentation and myeloid chemotaxis genes. These studies show that OV enhances survival and anti-brain-tumor immunity. They support MV and ICB as potentially being synergistic. They suggest translation control and perturbation of the myeloid compartment as strategies for enhancing intracellular MV proliferation and infection efficiency, respectively.
MDB-44. A TRANSFER LEARNING APPROACH FOR AUTOMATIC SEGMENTATION OF TUMOR SUB-COMPARTMENTS AND TUMOR HABITAT IN PEDIATRIC MEDULLOBLASTOMA
Authors: Rohan Bareja, Marwa Ismail, Doug Martin, Ameya Nayate, Ipsa Yadav, Murad Labbad, Benita Tamrazi, Ralph Salloum, Ashley Margol, Alexander Judkins, Sukanya Iyer, Peter de Blank, Pallavi Tiwari
Journal: Neuro-Oncology (2023)

Abstract PURPOSE Accurate delineation of pediatric medulloblastoma (MB) tumors is required for accurate surgical resection and efficient treatment planning. However, manual delineation is time consuming and prone to errors and inter-reader variability. We present the first attempt at automatic segmentation of MB tumors via a transfer learning approach that utilizes adult brain tumor segmentations to optimize segmentation of 1) the pediatric tumor habitat, comprising enhancing tumor (ET), necrosis/non-enhancing tumor (NET), and edema sub-compartments, and 2) the individual tumor sub-compartments. METHODS Our cohort consisted of 300 adult tumor MRI scans (BRATS) and 78 pediatric MB scans (46 training, 32 testing) with Gd-T1w, T2w, and FLAIR protocols. Training set subjects were collected from Children’s Hospital of Los Angeles (N=18) and Cincinnati Children’s Hospital Medical Center (N=28), whereas test set subjects were collected from Children’s Hospital of Philadelphia. Preprocessing included age-specific atlas registration, skull stripping, and bias correction. Then, using nnUnet framework, we trained 3D- deep learning U-net models on BRATS dataset for the tumor sub-compartments: ET, edema, and NET + necrosis, as well as the tumor habitat. Our initial learning rate was 0.01, with stochastic gradient descent as optimizer, and an average of dice loss and cross-entropy loss as the loss function. We then performed transfer learning using Models Genesis on the pediatric subjects. RESULTS Our segmentation model yielded mean dice scores of 0.87± .02 for tumor habitat, .83± .04 for ET, .742±.05 for edema, and .54±.11 for NET + necrosis, across fivefold cross-validation runs. For test set, our model yielded mean dice scores of 0.80 for the tumor habitat, 0.67 for ET, 0.54 for edema, and 0.28 for NET + necrosis. CONCLUSION Our transfer learning model shows promise in accurate automatic delineation of the MB tumor habitat and its individual sub-compartments, towards efficient surgical and treatment planning in MB tumors.
EPEN-08. COMBINED PDGFR INHIBITOR AXITINIB AND RETINOID TRETINOIN DECREASES PROLIFERATION AND HIGH-RISK NEOPLASTIC SUBPOPULATION PROPORTIONS PFA EPENDYMOMA
Authors: Andrew Donson, Enrique Grimaldo, Kent Riemondy, Andrea Griesinger, Vladimir Amani, Breauna Brunt, Angela Pierce, Nicholas Foreman
Journal: Neuro-Oncology (2023)

Abstract Ependymoma (EPN) is fatal in over 50% of children and has not seen any therapeutic improvements in over 30 years. Based on data from single-cell RNA sequencing (scRNAseq) and large-scale screening of FDA-approved oncology compounds in posterior fossa group A (PFA) EPN, we hypothesized that combination of PDGFR inhibitors and retinoids therapy will selectively deplete aggressive mesenchymal and undifferentiated EPN subpopulations resulting in therapeutic benefit. In vitro screening of a panel of three receptor PDGFR inhibitors (PDGFRIs) and nine retinoid analogues in high-risk chromosome 1q+/6q- PFA cell lines MAF-811 and MAF-928 was performed to identify those drugs with (i) anti-proliferative effect (tritiated thymidine incorporation and live-cell imaging), (ii) depletion of high-risk associated neoplastic subpopulations (qRT-PCR using subpopulation specific markers and scRNAseq), and (iii) synergistic effects. PDGFRIs axitinib and pazopanib and retinoids tazarotene, adapalene and tretinoin showed superior potency versus other analogues. qRT-PCR showed that tazarotene and axitinib demonstrated beneficial subpopulation perturbation. Combination of the top two PDGFRIs (axitinib and pazopanib) and retinoids (tazarotene and tretinoin) demonstrated that axitinib combined with tretinoin provided the strongest synergistic anti-proliferative effect and depletion of high-risk-associated undifferentiated subpopulations. More definitive scRNAseq subpopulation analysis revealed a reduction of mesenchymal cells in MAF-811 in response to combined axitinib/tretinoin treatments. In both MAF-811 and MAF-928 there was a net increase in the proportion of differentiated subpopulations, which are associated with a more favorable clinical outcome, in response to combined axitinib/tretinoin, collectively supporting our original hypothesis. These results demonstrate that combined RTKi axitinib and retinoid tretinoin treatment has a synergistic anti-proliferative effect and reduction of high-risk subpopulation proportions. The effect of combined axitinib and tretinoin on survival and subpopulation perturbation is now being explored in vivo.
BIOL-04. FROM MSWI/SNF’S ROLES IN PROTEIN SYNTHESIS TO NEW THERAPEUTIC OPPORTUNITIES
Authors: Capucine Van Rechem
Journal: Neuro-Oncology (2023)

Abstract The chromatin remodeler complexes mammalian SWI/SNF (SWItch/Sucrose Non-Fermentable) are altered in more than 40% of cancers and are involved in therapeutic resistance. In children, SMARCB1 is mutated in 95% of rhabdoid tumors, and the remaining 5% present mutations in SMARCA4. These tumors are typically identified in children younger than three years old and have a very poor prognosis with a survival under one year following diagnosis. SMARCB1 expression is also lost in more than 90% of epithelial sarcomas, a rare and aggressive tumor affecting young adults, and in 50% of pediatric chordomas. Additional mSWI/SNF subunits are also highly mutated in childhood cancers such as ARID1A and ARID1B in neuroblastomas, the most common solid tumor in children, and the ARID subunits and SMARCA4 in medulloblastomas, the most common brain cancer in children. To date, mSWI/SNF roles in normal and cancer cells are still largely undetermined and focus on nuclear functions. However, our assessment of genetic dependencies and drug sensitivity screens revealed that cancer cells mutated for mSWI/SNF are genetically dependent and exclusively sensitive to translation factors and translation pathway inhibitors. We demonstrate that mSWI/SNF complexes are extensively localized in the cytoplasm and that they interact with the translation initiation machinery. Furthermore, short-term inhibition, depletion and cancer mutations of specific subunits alter protein synthesis and increase sensitivity to translation inhibitors. Most mutations in these complexes being considered loss of function, these results suggest a potential therapeutic opportunity for diseases presenting mutations in these complexes. In conclusion, our work demonstrates the chromatin remodelers mSWI/SNF have direct roles in translation that will not only be relevant for the molecular understanding of cancer but also lead to new therapeutic opportunities.
Early Liver Specialist Consultation is Associated With Faster Biochemical Resolution of Severe Immune Checkpoint Inhibitor–Induced Hepatitis
Authors: Michael Li, Danny Wong, Jordan S. Sack, Alexander S. Vogel, F. Stephen Hodi, Lawrence Fong, Jennifer C. Lai, Shilpa Grover, Stephen D. Zucker
Journal: Journal of the National Comprehensive Cancer Network (2023)

Background: We evaluated the impact of gastroenterology/hepatology consultation, as recommended by guidelines, on the management of severe immune checkpoint inhibitor (ICI)–induced hepatitis. Methods: We conducted a multicenter, retrospective cohort study of 294 patients who developed grade ≥3 (alanine aminotransferase [ALT] &gt;200 U/L) ICI-induced hepatitis, with early gastroenterology/hepatology consultation defined as occurring within 7 days of diagnosis. The primary outcome was time to ALT normalization (≤40 U/L), and the secondary outcome was time to ALT improvement to ≤100 U/L. Results: A total of 117 patients received early consultation. In the 213 patients with steroid-responsive hepatitis, early consultation was not associated with faster ALT normalization (hazard ratio [HR], 1.12; 95% CI, 0.83–1.51; P =.453). A total of 81 patients developed steroid-refractory hepatitis, with 44 (54.3%) receiving early consultation. In contrast to the patients whose hepatitis responded to steroid treatment, early consultation in those with steroid-refractory disease was associated with faster ALT normalization (HR, 1.89; 95% CI, 1.12–3.19; P =.017) and ALT improvement to ≤100 U/L (HR, 1.72; 95% CI, 1.04–2.84; P =.034). Notably, additional immunosuppressive therapy for steroid-refractory disease was initiated sooner after diagnosis in the early consult group (median 7.5 vs 13.0 days; log-rank P =.001). When time to additional immunosuppression was added as a covariate to the Cox model in mediation analysis, early consultation was no longer associated with time to ALT normalization (HR, 1.39; 95% CI, 0.82–2.38; P =.226) or with time to ALT improvement to ≤100 U/L (HR, 1.25; 95% CI, 0.74–2.11; P =.404). Time to additional immunosuppression remained associated with faster ALT normalization and faster ALT improvement to ≤100 U/L in the model, suggesting that the faster hepatitis resolution in the early consultation group was primarily attributable to earlier initiation of additional immunosuppression. Conclusions: Early gastroenterology/hepatology consultation is associated with faster resolution of biochemical abnormalities in patients with steroid-refractory hepatitis. This beneficial effect appears to be mediated by earlier initiation of additional immunosuppressive therapy in those receiving early consultation.